Heterocyclic compounds

Abstract

The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

We claim: 
     
       1. A compound of formula I ##STR13## wherein R 1  and R 2  independently are hydrogen, halogen, trifluoromethyl, hydroxy, C 1-6  -alkyl or C 1-6  -alkoxy; Y is --CH 2  --N--CH 2  --, --CH 2  --N--CH 2  --, --(C═O)--N--CH 2  --, or --CH 2  --N--(C═O)--, wherein only the underscored atoms participate in the ring system;   X is --O--, --S--, --O--CH 2  --, --CH 2  --O--, --S--CH 2  --, --CH 2  --S--, or --(S═O)--, provided that the ring containing X and Y contains at least 8 members;   p is 0 or 1;   q is 0 or 1;   r is 1, 2 or 3;   m is 1 or 2;   n is 1 when m is 1 and n is 0 when m is 2;   R 3  and R 4  each represents hydrogen or may--when m is 2--together represent a bond; and   R 5  is --OH or C 1-6  -alkoxy; or a pharmaceutically acceptable salt thereof.     
     
     
       2. A compound according to claim 1 wherein R 1  and R 2  independently represent hydrogen, halogen or C 1-6  -alkoxy. 
     
     
       3. A compound according to claim 2 wherein R 1  and R 2  are hydrogen. 
     
     
       4. A compound according to claim 1 wherein r is 2. 
     
     
       5. A compound according to claim 1 wherein m is 2. 
     
     
       6. A compound according to claim 1 wherein R 5  is --OH. 
     
     
       7. A compound according to claim 1 which is: (R)-1-(3-(11,12-Dihydro-10H-dibenz b,g! 1,5!oxazocin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;   (R)-1-(3-(11,12-Dihydro-10H-dibenzo b,g! 1,5!thiazocin-11-yl)-1-propyl)-3-piperidinecarboxylic acid;   (R)-1-(3-(6,7-Dihydro-5H-dibenz b,g! 1,5!oxazocin-6-yl)-1-propyl)-3piperidinecarboxylic acid; or a pharmaceutically acceptable salt thereof.     
     
     
       8. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically carrier or diluent. 
     
     
       9. The pharmaceutical composition according to claim 8 wherein the compound is present in an amount between 0.5 mg and 1000 mg per unit dose. 
     
     
       10. A method of treating diabetic neuropathy, migraine, neurogenic inflammation, or rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 1. 
     
     
       11. A method of treating insulin resistance in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 1. 
     
     
       12. A method of treating diabetic neuropathy, migraine, neurogenic inflammation, or rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 8. 
     
     
       13. A method of treating insulin resistance in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 8. 
     
     
       14. A compound of formula I ##STR14## wherein R 1  and R 2  independently are hydrogen, halogen, trifluoromethyl, hydroxy, C 1-6  -alkyl or C 1-6  -alkoxy; Y is --O--CH--CH 2  --, --CH 2  --CH--O--, --S--CH--CH 2  -- or --CH 2  --CH--S-- wherein only the underscored atoms participate in the ring system;   X is --N(R 8 )--(C═O)--, --(C═O)--N(R 8 )--, or --N(R 9 )-- wherein R 8  and R 9  independently are hydrogen or C 1-6  -alkyl, provided that the ring containing X and Y contains at least 8 members;   p is 0 or 1;   q is 0 or 1;   r is 1, 2 or 3;   m is 1 or 2;   n is 1 when m is 1 and n is 0 when m is 2;   R 3  and R 4  each represents hydrogen or may--when m is 2--together represent a bond; and   R 5  is --OH or C 1-6  -alkoxy; or a pharmaceutically acceptable salt thereof.     
     
     
       15. A compound according to claim 14 wherein R 1  and R 2  independently represent hydrogen, halogen or C 1-6  -alkoxy. 
     
     
       16. A compound according to claim 15 wherein R 1  and R 2  are hydrogen. 
     
     
       17. A compound according to claim 14 wherein r is 2. 
     
     
       18. A compound according to claim 14 wherein m is 2. 
     
     
       19. A compound according to claim 14 wherein R 5  is --OH. 
     
     
       20. A pharmaceutical composition comprising a compound according to claim 14 together with a pharmaceutically carrier or diluent. 
     
     
       21. The pharmaceutical composition according to claim 20 wherein the compound is present in an amount between 0.5 mg and 1000 mg per unit dose. 
     
     
       22. A method of treating diabetic neuropathy, migraine, neurogenic inflammation, or rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 14. 
     
     
       23. A method of treating insulin resistance in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 14. 
     
     
       24. A method of treating diabetic neuropathy, migraine, neurogenic inflammation, or rheumatoid arthritis in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 20. 
     
     
       25. A method of treating insulin resistance in a subject in need of such treatment comprising administering to the subject a pharmaceutical composition according to claim 20.